Pharmaceuticals & Vitamin D : Neurological & mental health

Pharmaceuticals & Vitamin D Portfolios


Compounds and Methods for Modulating Frataxin Expression in Friedreich’s Ataxia

UW–Madison researchers have generated new chimeric complexes that selectively increase FXN mRNA production to eliminate the physiological cause of Friedrich’s Ataxia. The synthetic transcription elongation factors (Syn-TEFs) of the present invention comprise a bromodomain inhibitor (such as Brd4), bound to a linker (such as PEG), which is further bound to a polyamide designed to target a gene sequence of interest near the repeats (see image below). Mechanistically, the complex binds selectively to the DNA near the triplet repeats in FRDA patients, and then the linked bromodomain inhibitor binds BRD4 and thereby recruits the elongation machinery to restart the paused transcription complex.

The inventors observed a 4.3-fold improvement at 500 nM after 1 day, which should be sufficient for real improvement, since FRDA carriers only have 40% of normal expression and show no symptoms. Increasing the dose to 1 μM increased FXN mRNA 8.5-fold after 1 day, with 3-fold improvement after only 6 hours.

Retinoic Acid: A New Treatment for Sleep Apnea and Hypopnea

UW–Madison researchers have developed a new method for treating sleep apnea and hypopnea with retinoic acid.

A patient can be given a retinoid or retinoic acid receptor agonist such as all-trans RA (ATRA), 13-cis RA (isotretinoin) or 9-cis RA (alitretinoin). These compounds target the mechanisms that cause sleep apnea in two ways. First, they increase the respiratory drive (urge to breathe). Additionally, they reduce the apneic threshold (the level of CO2 necessary for the induction of breath) to normal levels.

Treatment of Fragile X Syndrome Using Nutlin-3

UW–Madison researchers have discovered that Nutlin-3, a candidate antitumor drug, and its derivatives may be useful for treating patients with FXS or other intellectual disability. This is the first time that Nutlin-3 has been shown to inhibit adult neural stem cell proliferation and rescue cognitive deficits in a FXS mouse model.

Nutlin-3 is a small molecule MDM2-p53 pathway inhibitor developed in 2004. The researchers use <10x dosage for FXS compared to the dosage used for cancer treatment.

Peptides to Treat Alzheimer’s Disease

UW–Madison researchers have developed a new strategy to design peptides that could be turned into therapeutics to treat or halt the progression of Alzheimer’s disease. The cyclized (ring-shaped) peptides are derived from transthyretin (TTR), a protein found in cerebrospinal fluid that is known to bind to Aβ and inhibit its toxicity in vitro and in vivo. The new peptides mimic both the sequence and the hairpin structure of transthyretin’s Aβ binding domain.

Treating Absence Epilepsy with Ganaxolone

UW–Madison researchers have developed a method for treating absence epilepsy with the drug ganaxolone, a synthetic neurosteroid analog that modulates GABAA receptors. The drug has shown promise for treating other forms of epilepsy but has not been recommended for absence epilepsy until now.

The researchers have found that in low doses the drug provides an optimal amount of tonic inhibition that restores function and reduces symptoms in a mouse model. The drug may be particularly useful for treating young patients whose condition is characterized by a reduction in tonic inhibition.

Enzyme Aids Intranasal Drug Delivery

UW–Madison researchers have developed a method to enhance intranasal drug absorption using a naturally occurring endopeptidase, called matrix metalloproteinase-9 (MMP-9). This enzyme makes the nasal epithelium more permeable to drugs by degrading type IV collagen. Nasal spray or drops containing MMP-9 can be administered at the same time or prior to a drug to improve its absorption.

New Treatment for Restenosis

UW–Madison researchers have developed an anti-restenosis formula made of insulin and connective tissue growth factor (CTGF). CTGF is a large protein known to help grow and remodel smooth vessel muscle after damage. The combination of CTGF and insulin increases levels of elastic collagen (type III) to promote healthy healing. The composition can be applied as an external wrap at the site of surgery.

Treating Multiple Sclerosis with UV Light

UW–Madison researchers have developed a method for suppressing MS symptoms by irradiating a patient with a narrow band of ultraviolet (UV) light. The light has a wavelength between about 300-315 nm. Patients could be irradiated using commercially available lamps or blankets. A typical treatment regimen could be 10-30 minutes of exposure for several days.

BACE1 Inhibitors Reduce β-Amyloid Production, Provide Potential Treatment for Alzheimer’s Disease

The UW–Madison researcher now has identified two compounds that can downregulate BACE1 levels and the rate of β-amyloid production and thus may be potential therapeutics for Alzheimer’s disease. These compounds inhibit the activity of ATase1 and ATase2.

Benzodiazepine Derivatives with Reduced Side Effects for Treatment of Neuropathic Pain

Researchers at the University of Wisconsin-Milwaukee have developed new benzodiazepine derivatives useful in the treatment of neuropathic pain with reduced sedative and ataxic effects. GABA is the major inhibitory neurotransmitter in the central nervous system. Non-selective benzodiazepine drugs, such as valium, act by enhancing the inhibitory effects of GABA at GABAA receptors in the CNS. These drugs broadly target GABAA receptors containing a1, a2, a3, or a5 subunits.

Recently, it was discovered that the various effects of non-selective benzodiazepines are specifically mediated through certain a subunit-containing GABAA receptor populations in the brain. a1-containing GABAA receptors control sedation, whereas the anti-anxiety and anti-pain activity works mainly through a2 and a3 receptors. a5 receptors play critical roles in learning and memory consolidation.

The inventors of this technology have produced GABAA receptor agonists specific for a2 and a3 receptors. Because the compounds do not affect a1 receptors, they have significant neuropathic pain protection without sedative and ataxic effects. In addition, the compounds are anxiolytic and anti-convulsant. The inventors are carrying out pre-clinical testing of these compounds by conducting in vitro studies and animal studies in rats, mice and monkeys. These compounds were found to have significant neuropathic pain protection in mice and rats without causing sedation, muscle relaxation or ataxic effect.

Borane-Protected Phosphine Molecules Save Cells from Death and Damage

UW–Madison researchers have developed a method for protecting cells from neurodegenerative injury, radiation damage and other causes of cell death.  The method involves exposing neuronal, endothelial or other mammalian cells to one or more of several borane-protected phosphine molecules created by the researchers.  These protective molecules have good cell permeability and chemical stability and are useful for treating or preventing cell-death related diseases and conditions in human and non-human animals.

Novel Subtype of Botulinum Toxin For Pharmaceutical Use

UW–Madison researchers have isolated a novel plasmid found in a C. botulinum type A strain that is not neutralized by antibodies. The plasmid encodes genes for subtypes BoNT/A3 or BoNT/A4 and BoNT/B. The neurotoxins can be purified and formulated into pharmaceuticals or vaccines.

Anti-Anxiety Pharmaceuticals with Reduced Side Effects

A team of researchers at UW-Milwaukee have developed novel benzodiazepine derivatives that offer increased binding sensitivity at GABA type A receptors while decreasing the negative side effects associated with these therapeutics. These orally-active derivatives, and salts thereof, provide enhanced anxiolytic activity with little or no sedative, hypnotic or muscle relaxing effects. These compounds were found to reduce situational anxiety in rats without causing significant sedation, muscle relaxation or ataxic effects. These benzodiazepine derivatives offer hope for more effective treatment of anxiety disorders in the future.

Method of Targeting Pharmaceuticals to Motor Neurons

UW-Madison researchers have developed a method for delivering therapeutic drugs to motor neurons. This method could be used to treat botulism, which is caused by botulinum neurotoxin, a potentially serious biological warfare agent. It involves synthesizing a therapeutic molecule covalently bound to a polymeric delivery vehicle and conjugating it to a botulinum neurotoxin heavy chain. The botulinum neurotoxin heavy chain acts as a vehicle for delivery of pharmaceuticals to motor neurons.